Anti-inflammatory pharmaceutical compositions and methods of administration

ABSTRACT

A composition for injection into a host is provided according to the embodiments of the present application. The composition consists of microparticles consisting essentially of an opioid antagonist and a polymeric binder selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and polyphosphazines; an injection vehicle, wherein said injection vehicle consists of water, a viscosity enhancing agent, a wetting agent, and a tonicity adjusting agent; and a steroidal anti-inflammatory agent.

This application claims priority to U.S. Provisional Application Ser.No. 62/547,378 filed on Aug. 18, 2017.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical composition whichcontains active ingredients and is effective as a self-sustainingdelivery mechanism for its own delivery for desired extended periods oftime. More particularly, this invention relates to an injectablecomposition having anti-inflammatory property characterized withimproved injectability and in situ sustained release formulation,preferably in excess of thirty days or more, and more preferably up toand exceeding ninety days.

BACKGROUND ART

Substance addiction typically follows a course of tolerance, withdrawal,compulsive drug taking behavior, drug seeking behavior, and relapse.Addictive substances include alcohol, caffeine, nicotine, cannabis(marijuana) and cannabis derivatives, opiates and other morphine-likeopioid agonists such as heroin, phencyclidine and phencyclidine-likecompounds, sedative ipnotics such as benzodiazepines and barbituratesand psychostimulants such as cocaine, amphetamines andamphetamine-related drugs such as dextroamphetamine andmethylamphetamine. Substance abuse and addiction are public healthissues. They have significant social and economic impact on both theaddict and society by playing a major role in violent crime and thespread of infectious diseases. Amongst all these substance addictions,opiate-opioid addiction is the most concerned drug issues today in theU.S.

While subtle, the distinction between opioids and opiates issignificant. An opiate is a drug naturally derived from the floweringopium poppy plant. Examples of opiates include heroin, morphine andcodeine. On the other hand, the term opioid is a broader term thatincludes opiates and refers to any substance, natural or synthetic, thatbinds to the brain's opioid receptors—the parts of the brain responsiblefor controlling pain, reward and addictive behaviors. Some examples ofsynthetic opioids include the prescription painkillers hydrocodone(Vicodin) and oxycodone (OxyContin), as well as fentanyl and methadone.While opioid/opiate medications are prescribed to treat pain andsometimes for other health problems such as severe coughing, these drugsalso affect the brain to increase pleasant feeling. Often the case theseprescription opioid/opiate drugs would be misused and even abused by thepeople who want to pursue such pleasant feeling. Addiction is not likelyto develop in a person using medication properly under a doctor's care.Addiction usually through misuse and/or abuse.

According to the World Health Organization, an estimated 13 millionpeople abuse opiates worldwide, including 9 million heroin addicts. Morethan 25% of opiate abusers die from suicide, homicide, or an infectiousdisease, such as HIV and hepatitis, within 10-20 years of becomingaddicted. Tolerance and physical dependence can develop within two tothree days.

The goals for treatment of opiate/opioid addiction, as with other typesof substance addictions, are to discontinue the use of the opiate/opioidwhile minimizing painful withdrawal symptoms and preventing relapse.Current treatments involve replacing the addictive drug with asubstitution of an opioid/opiate receptor agonist or mixedagonist/antagonist. An alternative approach consists of the use of anopioid receptor antagonist to block the effect of the agonist.

An agonist is a drug that activates certain receptors in the brain. Fullagonist opioids/opiates activate the opioid receptors in the brain fullyresulting in the full opioid/opiate effect. Example of full agonists areheroin, fentanyl, methadone, morphine, oxycodone, hydrocodone, opium andthe like.

An antagonist is a drug that blocks opioids by attaching to the opioidreceptors without activating them. Antagonists cause no opioid/opiateeffect and block full agonist opioids/opiates. Examples are naltrexoneand naloxone. By blocking the effects of agonist opiates, opiateantagonists also prevent the development of physical dependence andtolerance to opiate drug, such as heroin.

There are partial agonists which cause less conformational change andreceptor activation than full agonists. At low doses, both full andpartial agonist may provide similar effects to their full agonistcousins. However, when the dose of partial agonists increases, theanalgesic activity will plateau, and further increases in doses will notprovide additional relief but may increase the adverse effects. Examplesof partial agonists include buprenorphine, butorphanol and tramadol.

There are mixed agonists/antagonists, which demonstrate varying activitydepending on the opioid receptor but also varying on the dose. Examplesinclude buprenorphine, butorphanol, nalbuphine, and pentazocine. And,some opioids are agonists at 1 or more opioid receptors but alsoantagonist at other opioid receptors.

One preferred antagonist used in the treatment of former heroin addictsis naltrexone (N-cyclopropylmethylnoroxy morphone). Naltrexone therapyprovides for the efficient blockade of opioid receptors and is avaluable tool in treating opiate addiction in addition to behavioraltherapy and other approaches. Naltrexone, such as some opiateantagonists, provides no euphoric effects and there are no observablepharmacological consequences when a patient stops taking the drug. Fornaltrexone treatment to be effective, sufficient levels of the drug mustbe maintained in the patient for a substantial period of time. Thistypically requires the patient to self-administer dosages of the drugseveral times a week. Despite these positive outcomes associated withoral naltrexone treatment, non-compliance with oral naltrexone formulaehas been a major impediment to achieving positive clinical outcomes fora significant number of patients.

A major problem with the use of opiate antagonists, such as naltrexone,in the treatment of opiate addiction has been patient compliance. Onesolution for improving patient compliance and concomitant rehabilitationis the parenteral in situ sustained release drug delivery of antagonistsuch as naltrexone over a desirably long period of time. One of the drugproprietor, Vivitrol, has formulated an injectable suspension ofnaltrexone which is advertised to have extended release up to 28 days.The applicant however found out that Vivitrol can only last for 21 days.

Also, for injectable naltrexone formulation, the effect of foreign bodyresponse must be taken into consideration. The human immune response to‘non-self’ delivery formulations and vehicles typically manifests in theform of an inflammatory response, which can increase the release rate ofthe pharmaceutical ingredient due to increased local blood flow andmacrophage infiltration. For long-acting naltrexone, local inflammationin response to drug has been noted in multiple studies. However, thisexceeds the effect of the simple presence of the formulation itself andnaltrexone itself has been found to increase inflammation in animalstudies. Clinically, Naltrexone-injected Vivitrol™ inflammatoryreactions have been implicated in the development of eosinophilicpneumonia, as well as, severe side-reactions, including death. Due tothese complications, it is best to provide control of the inflammatoryreaction, in conjunction with NTX, by co-delivery of ananti-inflammatory agent.

Therefore, there is a need in the art for a composition which can reduceinflammatory complications while also extend the duration of long-actingpreparations. There is also a particular need in the art for aninjectable composition comprising of microparticle suspensions which canreduce inflammatory reactions during administration and is featured byin situ sustained release of the composition.

SUMMARY OF THE INVENTION

The present invention relates to a composition for injection into ahost, the composition consists opioid antagonist, which is useful in thetreatment of substance abuse and addictive or compulsive behaviors. Thusit can be administered non-surgically and therefore less invasive.Further it relies less on patient compliance. In one aspect, theinjectable composition of the present invention has improvedinjectability by providing microparticle form of opioid antagonist andconsisting specific polymeric binder. The composition also includes aninjection vehicle, wherein said injection vehicle consists of water, aviscosity enhancing agent, a wetting agent, and a tonicity adjustingagent. The composition further includes steroidal anti-inflammatoryagent. The composition includes the steroidal anti-inflammatory agentand microparticle encapsulating the opioid antagonist which collectivelyattain an effect of prolonging the duration of release of the agentsubstances, for example up to ninety days and longer.

Preferably, the opioid antagonist is selected from the group consistingof naltrexone, buprenorphine and salts thereof.

Preferably, the microparticles are suspended in said injection vehicleat a concentration of more than about 30 mg/ml and up to about 300 mg/mlto form a suspension, wherein a fluid phase of said suspension has aviscosity greater than 30 cp and less than 600 cp at 20° C., wherein theviscosity of said fluid phase of said suspension provides injectabilityof the composition into the host through a needle ranging in diameterfrom 18-22 gauge.

Optionally, the composition contains microparticles encapsulating boththe opioid antagonist and the anti-inflammatory agent.

In another aspect of this invention, there is provided a composition forinjection into a host, the composition comprises a biodegradablethermoplastic polymer, a biocompatible, polar solvent and an opiateantagonist or a pharmaceutically acceptable salt thereof. Thecomposition may be transformed into implant by contact with water, bodyfluid, or other aqueous medium. Further the composition comprises asteroidal anti-inflammatory agent which can prolong the duration ofrelease of the agent substances.

The biodegradable thermoplastic polymer can be present in any suitableamount, provided the biodegradable thermoplastic polymer is at leastsubstantially insoluble in aqueous medium or body fluid. Preferably thebiodegradable thermoplastic polyester is present in about 5 wt. % toabout 95 wt. % of the composition, or is present about 15 wt. % to about70 wt. % of the composition, or is present in about 25 wt. % to about 50wt. % of the composition.

Preferably, the biodegradable thermoplastic polymer has an averagemolecular weight of about 5,000 Daltons to about 40,000 Daltons, or morepreferably about 10,000 Daltons to about 20,000 Daltons.

The composition also includes a biocompatible, polar organic liquid. Thebiocompatible polar liquid can be an amide, an ester, a carbonate, anether, a sulfonyl, or any other organic compound that is liquid atambient temperature and is polar. The organic liquid may be veryslightly soluble to completely soluble in all proportions in body fluid.While the organic liquid generally should have similar solubilityprofiles in aqueous medium and body fluid, body fluid is typically morelipophilic than aqueous medium. Consequently, some organic liquids thatare insoluble in aqueous medium should be at least slightly soluble inbody fluid. These examples of organic liquid are included within thedefinition of organic liquids.

Preferably, the organic liquid comprises N-methyl-2-pyrrolidone,2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylenecarbonate, caprolactam, triacetin, or any combination thereof. Morepreferably, the organic liquid is N-methyl-2-pyrrolidone. Preferably,the polar organic liquid is present in about 10 wt. % to about 90 wt. %of the composition or is present in about 30 wt. % to about 70 wt. % ofthe composition

The opiate antagonist or pharmaceutically acceptable salt thereof ispresent in about 1 wt % to about 30 wt % of the composition; preferablybetween 5 wt % and 25 wt %; more preferably between 8 wt % and 22 wt %.Preferably, the opiate antagonist is selected from the group consistingof naltrexone, buprenorphine and salts thereof.

The composition is formulated as an injectable delivery system. Thecomposition preferably has a volume of about 0.10 mL to about 2.0 mL orpreferably about 0.20 mL to about 1.0 mL. The injectable composition ispreferably formulated for administration about once per month, aboutonce per three months, or about once per four months, to about once persix months. Preferably, the composition is a liquid or a gelcomposition, suitable for injection into a patient. The composition mayhave the property of production of minimal tissue necrosis when injectedintramuscularly or intravenously.

Thus it can be administered non-surgically and therefore less invasive.Further it relies less on patient compliance.

Excipients, release modifiers, plasticizers, pore forming agents,gelation liquids, non-active extenders, and other ingredients may alsobe included within the buprenorphine sustained release delivery system.Upon administration of the flowable composition, some of theseadditional ingredients, such as gelation liquids and release modifiersshould remain with the composition, while others, such as pore formingagents should separately disperse and/or diffuse along with the organicliquid.

In one embodiment, a method is provided for treating a patient having anopioid dependency comprising parenterally administering to the patient atherapeutically effective amount of a composition comprisingmicroparticles consisting an opiate antagonist or a pharmaceuticallyacceptable salt thereof, a biodegradable polymer and a steroidalanti-inflammatory agent, wherein the active ingredient and/or the agentrelease delivering therapeutically effective dosage from about 0.1 toabout 10 milligrams (mg) of the opiate antagonist or pharmaceuticallyacceptable salt thereof per day, or preferably from about 1 to about 5milligrams (mg) of the opiate antagonist or pharmaceutically acceptablesalt thereof per day. The therapeutically effective dosage of the opiateantagonist or pharmaceutically acceptable salt thereof may be achievedwithin about five days after administration of the composition, orpreferably, within about one day after administration of thecomposition. The therapeutically effective dosage of the opiateantagonist or pharmaceutically acceptable salt thereof may be deliveredfor at least about 28 days after administration of the composition, orpreferably for at least about 45 days after administration of thecomposition, or preferably for at least about 60 days afteradministration of the composition, or preferably for at least about 90days after administration of the composition.

Parenteral controlled release systems offer an advantage of decrease infrequency of injection. Parenteral dosage forms with prolonged actionare of medical and economic importance. The physician is interested inmaintaining therapeutic concentrations over a longer period of time andreducing the number of injections for a patient. Economically, onlywell-trained professional can administer injection, and if frequency ofadministration is reduced, the cost of therapy is decreased and time issaved.

The present invention advantageously reduces the inflammatory sideeffects from long-acting naltrexone formulations.

The present invention also advantageously provides a co-formulation ofopioid antagonist such as naltrexone and buprenorphine and steroidalagent to allow for extended duration of steroidal agent release.

The present invention further advantageously provides medicallyacceptable injectability rates for high concentration suspensions, andfor suspensions having large particle size.

The present invention further advantageously provides an efficientmethod of improving in vivo injectability without introducing microbialcontamination or compromising aseptic condition.

DEFINITION

Pharmaceutical/Biologically Active Substance

By “pharmaceutical/biologically active substance” or otherwise “activeingredient” as used herein is meant any conventional, experimental,novel or as yet unknown pharmaceutical, drug or biologically activesubstance for use in animals or humans. Some examples include, withoutlimitation: protein drugs such as insulin; desensitizing agents such asragweed pollen antigens, hay fever pollen antigens, dust antigen andmilk antigen; vaccines such as smallpox, yellow fever, distemper, hogcholera, fowl pox, antivenom, scarlet fever, diphtheria toxoid, tetanustoxoid, pigeon pox, whooping cough, influenza, rabies, mumps, measles,poliomyelitis, Newcastle disease, etc.; antiinfectives, such asantibiotics, including penicillin, tetracycline, chlortetracyclinebacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin,oxytetracycline, chloramphenicol, and erythromycin; sulfonamides,including sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine,sulfamerazine, and sulfisoxazole; anti-virals including idoxuridine; andother antiinfectives including nitrofurazone and sodium propionate;antiallergenics such as antizoline, methapyrilene, chlorophenaramine,pyrilamine and prophenpyridamine; antiallergenics such ashydrocortisone, cortisone, hydrocortisone acetate, dexamethasone,dexamethasone 21-phosphate, fluocinolone, triamcinolone, medrisone,prednisolone, prednisolone 21-phosphate, and prednisolone acetate;decongestants such as phenylephrine, naphthazoline, andtetrahydrazoline; miotics and anticholinesterases such as pilocarpine,eserine salicylate, carbachol, diisopropyl fluorophosphate, phospholineiodide, and demecarium bromide; such as atropine sulfate,cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine; sympathomimetics such as epinephrine; sedatives andhypnotics such as pentobarbital sodium, phenobarbital, secobarbitalsodium, codeine, (a-bromoisovaleryl)urea, carbromal; psychic energizerssuch as 3-(2 aminopropyl)indole acetate and 3-(2 amino butyl) indoleacetate; Tranquilizers such as reserpine, chloropromaline, andthiopropazate; androgenic steroids such as methyltestosterone andfluorymesterone; estrogens such as estrone, 17 B-estradiol, ethenylestradiol, and diethyl stilbesterol; progestational agents such asprogesterone, megestrol, melengestrol, chlormadinone, ethisterone,norethynodrel, 19-nor-progesterone, norethindrone, medroxyprogesteroneand 17 B-hydroxy-progesterone; Humoral agents such as theprostaglandins, for example PGE1, PGE2, and PGF2; antipyretics such asaspirin, sodium salicylate, and salicylamide; antispasmodics such asatropine, methantheline, papaverine, and methscopolamine bromide;antimalarials such as the 4-aminoquinolines, 8-aminoquinolines,chloroquine, and pyrimethamine; antihistamines such as diphenhydramine,dimenhydrinate, tripelennamine, perphenazine, and chlorophenazine;cardioactive agents such as dibenzohydroflumethiazide, flumethiazide,chlorothiazide, and aminotrate; nutritional agents such as vitamins,essential amino acids and essential fats, and veterinarypharmaceuticals.

Other drugs having the same or different physiological activity as thoserecited above can be employed in drug-delivery devices within the scopeof the present invention.

“Effective Amount” of Pharmaceuticals

Drugs can be in various forms, such as uncharged molecules, componentsof molecular complexes, or nonirritating, pharmacologically acceptablesalts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate,borate, acetate, maleate, tartrate, salicylate, etc. For acidic drugs,salts of metals, amines, or organic cations (e.g., quaternary ammonium)can be employed. Furthermore, simple derivatives of the drugs (such asethers, esters, amides, etc.) which have desirable retention a sustainedrelease characteristics but which are easily hydrolyzed by body pH,enzymes, etc., can be employed.

The amount of drug or bioactive substance incorporated in thedrug-delivery device of the invention can vary widely depending on theparticular drug, the desired therapeutic effect, and the time span forwhich it takes the composition to dissolve and/or release. Since avariety of the inventive devices in a variety of sizes and shapes areintended to provide complete dosage regimes for therapy for a variety ofmaladies, there is no critical upper limit on the amount of drugincorporated in the device. The lower limit also will depend on theactivity of the drug and the time span of its release from the device.Thus, it is not practical to define a range for the therapeuticallyeffective amount of drug to be release by the device.

The amount of drug to be dispensed in a specified time, will of course,depend on such factors as the particular application, the particulardrug, the age of the patient, etc. In general, what will constitute an“effective amount” will be known or easily ascertainable by thoseskilled in the art. Much of this type of data is published in theliterature or easily determined by routine experimentation. Examples ofthe published literature on effective amounts of progestin-typesteroids, in this case for topical application, can be found in Shipley,“Effectiveness of Topically Applied Progestational Agents,” Steroids 7(4): 341-349, (April 1966). In a like manner, the following literaturedescribes effective amounts of addictive drug antagonists: MARTIN, W.R., “Opioid Antagonists,” Pharmacological Reviews, Vol. 19, no. 4, pp.463-521 (1967) and references contained therein; FREEDMAN, A. M.,“Cyclazocine and Methadone in Narcotic Addiction,” The Journal of theAmerican Medical Association, Vol. 202, pp. 191-194 (Oct. 16, 1967).Also, the patents mentioned above often contain data on effectiveamounts for any particular application.

In addition to the control over delivery of drugs which can be obtainedthrough proper choice and design of the inventive formulation asdiscussed supra, the dosage administered by this formulation can becontrolled by the size and shape of the formulation device (such as sizeof microparticles/microspheres, size and shape of tablet/capsule of oralformulation, etc.), concentration of the drug in the device, density ofthe device, and nature of the carrier surface area, pore size, matchingof the carrier and drug, nature of the surroundings, etc. This is of aparticular advantage where it is desirable to deliver a metered amountof the drug over a specified period of time.

Of course, combinations of drugs and substances in addition to drugs canalso be incorporated into the inventive formulation device. For example,radioactive tracers such as carbon-14, nonradioactive tracers such asbarium sulfate, carriers which would transport the drug through skinsuch as dimethylsulfoxide and dimethylsulfone, water-soluble excipients,etc. could be incorporated with certain drugs for particularapplications. The amount of auxiliary agent used will depend, of course,on the specific agent, drug and carrier used to fabricate theformulation device as well as the purpose for incorporating theauxiliary agent.

“Microparticles” or “Microspheres”

By “microparticles” or “microspheres” is meant particles that contain anactive agent or other substance dispersed or dissolved within a polymerthat serves as a matrix or binder of the particle.

“Biodegradable” and “Biocompatible”

By “biodegradable” is meant a material that should degrade by bodilyprocesses to products readily disposable by the body and should notaccumulate in the body. The products of the biodegradation should alsobe biocompatible with the body. By “biocompatible” is meant not toxic tothe body, is pharmaceutically acceptable, is not carcinogenic, and doesnot significantly induce inflammation in body tissues. As used herein,“body” preferably refers to the human body, but it should be understoodthat body can also refer to a non-human animal body.

Other Definitions

By “weight %” or “% by weight” is meant parts by weight per hundredparts total weight of microparticle. For example, 10 wt. % active agentwould mean 10 parts active agent by weight and 90 parts polymer byweight. Unless otherwise indicated to the contrary, percentages (%)reported herein are by volume. By “controlled release microparticle” or“sustained release microparticle” is meant a microparticle from which anactive agent or other type of substance is released as a function oftime. By “mass median diameter” is meant the diameter at which half ofthe distribution (volume percent) has a larger diameter and half has asmaller diameter.

DETAILED DESCRIPTION

In its broadest sense, the present invention provides a novelpharmaceutical composition which contains an admixture of apharmaceutical/biologically active substance (active ingredient), ananti-inflammatory agent, and a pharmaceutically acceptable carrier. Thepharmaceutical composition is particularly suitable for parenteralinjection such as intravenous or intramuscular injection to a patientand effective for the delivery of therapeutically effective levels ofthe pharmaceutical/biological active substance over extended periods oftime, preferably in excess of ninety days. The pharmaceuticalcomposition is suitable for not only the parenteral administrations suchas intravenous (injection into a vein), subcutaneous (injection underthe skin), intramuscular (injection into a muscle), intraoperitoneal(injection into the peritoneum (body cavity)), intracardiac (injectioninto heart muscles or ventricles), intraarticular, intracavernous,inhalation (aerosols, infusion through the lungs), and percutaneous(absorption through intact skin), but also the enteral administrationssuch as oral, sublingual (dissolving the drug under the tongue), andrectal. Without limitation, the pharmaceutical composition can beprepared to formulations suitable for enteral administration listedabove by conventional means such as compression molding into surgicalimplant pallet, blending/granulation/compression in forming oral soliddose form (i.e. tablets/capsules), compression/fusion molding inpreparing suppositories), and pressure filling in preparing aerosolformulation; or non-conventional means which are to be discovered in thefuture.

Particularly, the pharmaceutical composition is prepared in aformulation suitable for parenteral administrations characterized within situ controlled release mechanism. More particularly, the compositionof present invention can be made in the forms ofmicroparticles/microspheres, liposomes and/or injectable gels.

Microparticles, Nano Encapsulation and Microcapsulations

Microparticulate drug delivery systems are an interesting and promisingoption when developing drug release control system. It significantlyincreases efficiency of drug delivery, improving the release profile anddrug targeting.

Therefore, the present invention also provide an injectable compositionshaving microencapsulated particles suspended in an injection vehicle. Inthe specific embodiments of the present invention, anti-addictiveagent-contained microparticles suspended in injection carrier with asteroidal anti-inflammatory agent, or an anti-addictive agent and asteroidal anti-inflammatory agent are both encapsulated in theparticles. The polymer is preferably biodegradable and biocompatible. Ingeneral, “microencapsulated particles” referred in this inventioncomprises polymer encapsulated microparticles, liposomes and relatedcompositions, micellar system encapsulated compositions, cyclodextranencapsulated compositions and the like. This invention is not limited topolymeric microspheres based drug delivery systems. Liposome basedsustained drug delivery disclosed or known in the art can also bedelivered using methods and compositions disclosed in this invention.Similar to liposomes, micellar drug delivery systems wherein the drug isencapsulated in a micelle formed in the water solution can also be usedand deposited using compositions and methods described in thisinvention. Applicant is of the view that manufacturing processes formicrospheres are often complex and difficult to control. As a result,there are often questions involving costs and batch-to-batch productuniformity. Likewise, liposome delivery system suffers fromdisadvantages like, high production cost, leakage of drug, short halflife and low solubility.

In accordance with a preferred aspect the present invention, there isprovided an opiate antagonist in the form of injectable suspension inwhich the active ingredient of antagonist is present in concentratedform as a self-sustaining delivery mechanism for its own delivering aneffective amount of an opiate antagonist over a prolonged or extendedperiod of time, preferably in excess of thirty days and more preferablyin excess of ninety days.

Pharmaceutical composition of the present invention are thereforeparticularly useful in the treatment of addiction to opiate-opioidabuse, and in the treatment of addictive or compulsive behaviors. Theterm addiction has been referred to as a recurring compulsion by anindividual to engage in some specific activity, despite harmfulconsequences to the individual's health, mental state or social life.That is to say, it is an uncontrolled, compulsive use or behavior.Embodiments of the present invention may thus be useful in treatingaddiction to opiate-opioid of abuse including both recreational drugsand medications alike. Examples of opiate-opioid drugs include, opiatesand other morphine-like opioid agonists such as heroin, phencyclidineand phencyclidine-like compounds, sedative ipnotics such asbenzodiazepines, methaqualone, mecloqualone, etaqualone and barbituratesand psychoactive stimulants (also known as psychostimulants) such ascocaine, amphetamines and amphetamine-related drugs such asdextroamphetamine and methylamphetamine. Other examples includehallucinogens such as LSD, psilocybin, and ecstasy. Examples ofaddictive medications include, e.g., benzodiazepines, barbiturates, andpain medications including alfentanil, allylprodine, alphaprodine,anileridine benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, codeine, cyclazocine, desomorphine, dextromoramide,dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofenitanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, (e.g., OxyContin™), oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propiram, propoxyphene sufentanil, tramadol, tilidine,salts thereof, mixtures of any of the foregoing, mixedμ-agonists/antagonists, and the like.

Other examples of addictive or compulsive behaviors that may be treatedin accordance with embodiments of the present invention includepathological gambling, sex addiction, addiction to pornography,compulsive overeating, compulsive overexercising, and compulsive use ofelectronic gadgets and devices such as electronic video games andsmartphones and communication devices such as Apple iPhone® devices.

Anti-addictive agents that may be included in the inventivepharmaceutical delivery systems include antagonists. These agents actupon receptors, typically in the brain (and which may also be present inone or more other organs such as liver, lungs and kidney) andcompetitively bind the receptor with higher affinity than the agonist,i.e., the substance of abuse. Thus, they effectively block the receptorso as to prevent the body from responding to the substance of abuse, orin the case of compulsive behavior, more generally by blocking thepositive reinforcing effect of the behavior. As explained herein, someantagonists useful in the present invention may also produce a weak orpartial agonist response. Partial agonists bind and activate a givenreceptor, but have only partial efficacy at the receptor relative to afull agonist. They may also be considered ligands which display bothagonistic and antagonistic effects—when both a full agonist and partialagonist are present, the partial agonist actually acts as a competitiveantagonist, competing with the full agonist for receptor occupancy andproducing a net decrease in the receptor activation observed with thefull agonist alone.

In some embodiments, the active agent includes an opioid antagonist. An“opioid antagonist” is an opioid compound or composition including anyactive metabolite of such compound or composition that in a sufficientamount attenuates (e.g., blocks, inhibits, prevents or competes with)the action of an opioid agonist. These agents exert their activity byacting on one or more opioid receptors. At least three types of opioidreceptors, mu, kappa, and delta opioid receptors, have been reported.Opioid antagonists are generally classified by their effects on theopioid receptors. Opioid antagonists may antagonize central receptors,peripheral receptors or both. Many opioid antagonists are not pureantagonists but also produce some weak opioid partial agonist effects,and can produce analgesic effects when administered in high doses toopioid-naive individuals. Examples of such compounds include nalorphine,and levallorphan. However, the analgesic effects from these drugs arelimited and tend to be accompanied by dysphoria, most likely due toaction at the kappa opioid receptor. Since they induce opioid withdrawaleffects in people who are taking, or have previously used, opioid fullagonists, these drugs are considered to be antagonists.

Naloxone and naltrexone are commonly used opioid antagonist drugs thatare competitive in that they bind to the opioid receptors with higheraffinity than agonists, but that do not activate the receptors. Thiseffectively blocks the receptor, preventing the body from responding toopiates and endorphins. Naloxone is one example of an opioid antagonistthat has no partial agonist effects. Instead, it is a weak inverseagonist at mu opioid receptors, and is used for treating opioidoverdose. However extremely powerful synthetic opioid drugs likefentanyl and its analogues, which are 50-100 times more powerful thanmorphine and up to 30-50 times as potent (and as deadly) as heroin, arefound to be resistant to naloxone lately. Therefore in the specificexamples, naltrexone is preferred.

Examples of other opioid antagonists that may be used according to theinvention include alvimopan, binaltorphimine, buprenorphine,cyclazocine, cyclorphan, cypridime, dinicotinate, beta-funaltrexamine,levallorphan, methylnaltrexone, nalbuphine, nalide, nalmefene,nalmexone, nalorphine, nalorphine dinicotinate, naloxonazine,naltrendol, naltrindole, oxilorphan, and pentazocine, or theirpharmacologically effective esters or salts, or free base forms thereof.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts of basic compoundscan be obtained by reacting the compound with an acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. For example,naltrexone hydrochloride is a pharmaceutically acceptable salt ofnaltrexone. Pharmaceutical salts of acidic compounds can be obtained byreacting the compound with a base to form a salt such as an ammoniumsalt, an alkali metal salt, such as a sodium or a potassium salt, analkaline earth metal salt, such as a calcium or a magnesium salt, a saltof organic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, and salts thereof with amino acids suchas arginine, lysine, and the like.

In the preferred embodiments, naltrexone is used as anti-addictiveagent. The term “naltrexone” may be used in a general way herein torefer to a free base of naltrexone, a pharmaceutically acceptablenaltrexone salt (including hydrates and anhydrous forms, e.g.,naltrexone hydrochloride dihydrate and anhydrous naltrexonehydrochloride), a naltrexone metabolite, a naltrexone isomer, analtrexone prodrug or mixtures thereof. Reference herein to “naltrexone”will be understood as encompassing all such forms, unless the contextclearly indicates otherwise. In yet another preferred embodiment,buprenorphine is used as the anti-addictive agent.

In some embodiments, the opioid antagonist includes a non-selective,mixed agonist-antagonist opioid receptor modulator. An example isbuprenorphine, marketed in the U.S. by Indivior Inc. under the tradenameSUBLOCADE. The buprenorphine of Sublocade, a mu-opioid receptor partialagonist and a kappa-opioid receptor antagonist is a buprenorphine freebase employing ATRIGEL™ drug delivery system at 18% by weight in apre-filled syringe. In yet another embodiment ATRIGEL™ can be employedand blended with other opioid antagonist such as naltrexone. Detailsabout The ATRIGEL™ drug delivery system will be discussed in the sectionof Pharmaceutically Acceptable Carrier below. After initial formation ofthe depot, buprenorphine is released by the breakdown (biodegradation)of the depot. In clinical trials, Sublocade provided sustainedtherapeutic plasma levels of buprenorphine over the one-month dosinginterval.

Opioid antagonists, and particularly naltrexone, may be useful in thetreatment of addiction to opioids and opiates (which although refer tonatural and synthetic compounds respectively, these terms are commonlyused interchangeably, and thus are used herein in a consistent manner).Opioids that may cause such addictive behavior include opioid agonists(natural, semi-synthetic and synthetic alike), partial opioid agonistsand mixed opioid agonist/antagonists. Examples of opioids that can beaddictive include morphine, codeine, methodone, fentanyl and heroin.Opioid antagonists may also be useful in the treatment of alcoholaddiction, nicotine addiction and in the treatment of addictive orcompulsive behaviors including pathological gambling, sex addiction, andaddiction to pornography, compulsive overeating, compulsiveoverexercising, compulsive overexercising, and compulsive use ofelectronic gadgets and devices such as electronic video games andsmartphones and communication devices such as Apple iPhone® devices.While not intending to be bound by theory, it is believed that opioidantagonists such as naltrexone act by blocking the positive reinforcingeffect of alcohol or the compulsive behavior, or in the case of alcohol,by blocking the positive reinforcing effect which results from therelease of endogenous opioids upon the consumption of alcohol.

The therapeutically effective amount of opioid antagonist contained inthe composition may vary, depending upon such factors as the solubilityof the opioid antagonist in the carrier, the volume of the compositionfor injection, and the desired time period over which release of thedrug is sought. In general, amounts of opioid antagonist (e.g.,naltrexone) effective for treatment ranges from about 200 mg to about1000 mg, and in some embodiments, about 200 mg to about 500 mg, or about200 to 300 mg, or about 300 to about 500 mg. Thus, the injectablecomposition may provide for in situ prolonged release of opioidantagonist (e.g., naltrexone) as to sustain therapeutic blood levelswhich are typically in the order of about 1 mg/ml blood, for about 2weeks to about 1 month, 6 weeks, or even about 2 months.

In some embodiments, the anti-addictive agent includes a cannabinoidreceptor antagonist. These agents are effective in the treatment ofaddiction to cannabinoids, nicotine and hallucinogens. The cannabinoidreceptors are a class of the G-protein coupled receptor superfamily.Their ligands are known as cannabinoids. There are currently two knownsubtypes, CB1 which is expressed mainly in the brain, but also in thelungs, liver, and kidney, and CB2, which is mainly expressed in theimmune system and in hematopoietic cells. It is also believed that thereare novel cannabinoid receptors that is, non-CB1 and non-CB2, which areexpressed in endothelial cells and in the CNS. Cannabinoid receptorantagonists may be selective for either the CB1 or CB2 receptor. Thepresent invention contemplates the use of either or both CB1 and CB2receptor antagonists.

Addictive substances (e.g., alcohol, opiates,Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and psychostimulants,including nicotine), against which the inventive compositions mayprovide treatment, elicit a variety of chronically relapsing disordersby interacting with endogenous neural pathways in the brain. Inparticular, they share the common property of activating mesolimbicdopamine brain reward systems, and virtually all abused drugs elevatedopamine levels in the nucleus accumbens. Cannabinoid-1 (CB1) receptorsare expressed in this brain reward circuit and modulate thedopamine-releasing effects of Delta(9)-THC and nicotine.

Rimonabant (SR141716), a CB1 receptor antagonist, blocks both thedopamine-releasing and the discriminative and rewarding effects ofDelta(9)-THC in animals. Although CB1 receptor blockade is generallyineffective in reducing the self-administration of cocaine in rodentsand primates, it reduces the reinstatement of extinguishedcocaine-seeking behavior produced by cocaine-associated conditionedstimuli and cocaine priming injections. Similarly, CB1 receptor blockadeis effective in reducing nicotine-seeking behavior induced byre-exposure to nicotine-associated stimuli. In human clinical trials,rimonabant was shown to block the subjective effects of Delta(9)-THC inhumans and prevents relapse to smoking in ex-smokers. Other examples ofcannabinoid receptor CB1 antagonists include rosanabant, taranabant andCP-945598.

Therapeutically effective amounts of these agents that may be present inthe injectable compositions generally range from about 100 to about 1000mg.

In some embodiments, the active agent includes a 5-hydroxytryptamine 3(5-HT3) receptor antagonist. These agents are known to exert ananti-emetic effect and thus are effective against nausea and vomiting.These agents may be effective in treating addiction to psychoactivestimulants such as cocaine and amphetamines and methamphetamines.Examples of 5-HT3 receptor antagonists that may be useful in the presentinvention include alosetron, azasetron, bemesetron, cilansetron,dolasetron, granisetron, indisetron, itasetron, ondansetron,palonosetron, propisetron, ramosetron, renzapride, tropisetron, andzatosetron. Therapeutically effective amounts of these agents that maybe present in the injectable compositions generally range from about 100to about 600 mg.

In some embodiments, the anti-addictive agent includes a partial agonistof the nicotinic acetylcholine receptor, and specifically the α4β2subtype of the receptor. An example is varenicline, marketed in the U.S.by Pfizer under the tradename CHANTIX. Varenicline has been reported toboth reduce cravings for and decrease the pleasurable effects ofcigarettes and other tobacco products, and through these mechanisms itcan assist patients in stopping smoking. Therapeutically effectiveamounts of these agents that may be present in the injectablecompositions generally range from about 100 to about 600 mg.

Anti-inflammatory Agents

For injectable naltrexone formulations, the effect of foreign bodyresponse must be taken into consideration. Anti-inflammatory agentspresent in the inventive compositions are effective to reduce blood flowto cellular elements, whether steroidal or non-steroidal, i.e.,non-steroidal anti-inflammatory delivery (NSAID, e.g., salicyclate,ketorolac, naproxen, ibuprofen).

In the development of the present invention, it has been found thatVivitrol™ only lasts for 21 days, instead of 28 days as reported.Surprisingly and unexpectedly, it has been found that the use of ananti-inflammatory compound, particularly a steroid, in admixturecombination with a pharmaceutical or biologically active substance,particularly an opiate antagonist, and a pharmaceutical carrier formedin an injectable suspension provides for unexpectedly long-lastingdosing times, such as, for example, up to approximately eighty days andlonger, thus providing for particularly efficacious drug deliveryperiods, for example, slow-release antagonist delivery foranti-addiction therapy as the case may be.

Without intending to be bound by any particular theory of operation,Applicant believes that the presence of the anti-inflammatory agentdecreases the inflammatory response caused by the injection and thepresence of a foreign substance, and that attraction of phagocytic cellsto the site of injection is reduced. Applicant also believes that thehydrophobicity of steroidal anti-inflammatory agent keeps water awayfrom the anti-addictive agent such as naltrexone, thus, maximizingamount of injected drug available for sustained absorption.

The application of medicines to the human body is a dynamic process. Inorder to achieve appropriate therapeutic effect, not only is dose andlocation important, but also time of application. This is due tooverlapping, and competing, mechanism involved with drug release,transport, absorption, and clearance. Optimally, medicine will beapplied in such a way as to maximize the therapeutic effect by ensuringan appropriate amount of time that the concentration of the drug ismaintained within the therapeutic host. Time-controlled, sequentialrelease is a key element for designing drug delivery systems which canallow for precise dosing in the absence of externally timed events suchas administration of extra doses. In-vivo, one of the driving influenceson release of drug is phagocytosis.

Phagocytosis is a process in which macrophages take up “invaders” suchas pathogens and viruses to protect the host from infection by them.This process of phagocytosis is disadvantageous in general forexhibition of an efficient pharmacological effect of particleformulations containing drug, because the uptake of particles bymacrophages reduces the extracellular drug concentration. It is known inthe art that drug particles formulations such as modification ofparticles by polyethylene glycol (PEG) forming a hydrated phase on thesurface of particles, enables long-lasting circulation of such particlesin the bloodstream by circumventing their uptake by macrophage cells.Alternatively and unexpectedly, Applicant discovered that the release ofnaltrexone can be controlled by application of steroidalanti-inflammatory agent. The mechanism (i.e. phagocytosis inmacrophages) is that the anti-inflammatory agent inhibits the whiteblood cell engulfing and digesting pathogens, cell debris and also otheralien particles (e.g. anti-addictive agent of naltrexone particles), andthereby prevents the uptake of naltrexone particles by macrophages.

More specific examples (a non-exhaustive list) of steroids useful hereininclude anti-inflammatory type of steroid such as glucocorticoids whichsuppress inflammation and immunity. This list of glucocorticoidsincludes but not limited to hydrocortisone (Cortef), cortisone,ethamethasoneb (Celestone), prednisone (Prednisone Intensol) andprednisolone (Orapred, Prelone).

The amount of anti-inflammatory compound may vary depending upon factorsas the amount of drug to be released in a desired time, and the volumeof the composition administered. In general, amounts ranging from about0.01% to about 99.9% by wt may be employed.

Pharmaceutically Acceptable Carrier

The pharmaceutically acceptable carrier (or vehicle) includes abiodegradable or bioerodible liquid. Both non-aqueous and aqueousliquids alike may be useful.

a. Injectable Suspension in Oil or Aqueous

The agents may be soluble in the carrier (in which case it may bereferred to as a solvent), thus forming an injection solution, orinsoluble in which case the injectable composition is in the form of asuspension or dispersion (in which case the carrier may be referred toas a suspension or dispersion medium).

Examples of non-aqueous carriers include edible oils typically vegetableoils. Examples of edible oils that may be useful in the presentinvention include cottonseed oil, corn oil, almond oil, ground nut cornoil, germ olive oil, germ olive oil, castor oil, and sesame oil.Derivatives of the oils, such as hydrogenated forms of these oils, mayalso be useful. In some embodiments, cottonseed oil, almond oil, sesameoil, or a corn oil is present. Peanut and olive oils are less preferred.In the case of aqueous suspensions, the compositions may also contain,in addition to water, a dispersing or suspending agent, examples ofwhich include synthetic and natural gums such as tragacanth, acacia,alginate, dextran, cellulose derivatives, (e.g., sodiumcarboxymethylcellulose and methylcellulose), polyvinyl-pyrrolidone, andgelatin.

The volume of carrier generally ranges from about 2 to about 10 ml, andin some embodiments, from about 2 to about 5 ml, and in yet otherembodiments, from about 3 to about 4 ml.

The composition is fluid to the extent that easy syringability exists.It also should be stable under the conditions of manufacture and storageand be preserved against the contaminating action of microorganisms suchas bacteria and fungi. Thus, a preservative may be present. Exemplarypreservatives include materials that inhibit bacterial growth, such ashydroxybenzoates (e.g., ethyl and propyl hydroxybenzoates such asNipagen™ and Nipasol™), alcohol (e.g., lower alkanols such as ethanol),antimicrobial agents, benzoic acid, sodium benzoate, benzyl alcohols,sorbic acid, parabens, isopropyl alcohol and others known to one ofordinary skill in the art. Proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion, and by the use ofsurfactants. Isotonic agents such as sugars, sodium chloride, orpolyalcohols such as mannitol and sorbitol, may also be present in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions can be prepared by incorporating thetherapeutic compound in the required amount in an appropriate solventwith one or a combination of ingredients enumerated above, as required,followed by sterilization (which can be conducted in accordance withstandard pharmaceutical techniques, such as radiation, heat and filtersterilization). Generally, dispersions are prepared by incorporating thetherapeutic compound into a sterile vehicle which contains a basicdispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze-drying which yield a powder of the activeingredient (i.e., the therapeutic compound) optionally plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

b. ATRIGEL™ Drug Delivery System

Biodegradable injectable in situ gel forming drug delivery systemsrepresent an attractive alternative to microspheres as parenteral depotsystems. It consists of biodegradable polymers dissolved in abiocompatible carrier. ATRIGEL™ is a proprietary biodegradableinjectable in situ gel forming drug delivery system that can be used forboth parenteral and site-specific drug delivery. The consists of abioerodable polymer (poly(DL-lactide-glycolide) (PLGA) copolymer)dissolved in biocompatible carrier (N-methyl-2-pyrrolidone (NMP)) in75:25 molar ratio. In the preferred embodiment of the composition of thepresent invention, it consists of any pharmaceutically efficaciousamount of the polymer and carrier, preferably, for example, about 5 wt %to about 95 wt % of biodegradable polymer and about 5 wt % to about 95wt % of biocompatible carrier. Pharmaceuticals may be blended into thisPLGA solution at the point of manufacture, or they may be added by thephysician at the time of use. The liquid product is injectedsubcutaneously or intramuscularly through a small gauge needle,whereupon displacement of the NMP carrier with water in the tissuefluids causes the PLGA to precipitate, forming a solid film or implant.If the pharmaceutical is incorporated into the polymer solution, itbecomes entrapped within the polymer matrix as it solidifies, and isthen released in a controlled manner as the polymer matrix erodes withtime in the body.

METHOD AND EXAMPLES

The following examples are provided to explain the invention, and todescribe the materials and methods used in carrying out the invention.The examples are not intended to limit the invention in any manner.

Example 1 Methods for Preparing Injectable Compositions

Methods for preparing injectable compositions in accordance with thepresent invention will now be described. In accordance with the presentinvention, microparticles are first mixed with an injection vehiclehaving suitable viscosity and wetting characteristics to achieve ahomogeneous mono-particulate suspension. The viscosity of the fluidphase of the suspension is then changed, preferably increased, toachieve a viscosity that inhibits suspension separation and cloggingunder conditions of normal clinical use. In accordance with one methodof the present invention, dry microparticles are mixed with an aqueousinjection vehicle to form a first suspension. The first suspension ismixed with a viscosity enhancing agent to form a second suspension. Theviscosity enhancing agent increases the viscosity of the fluid phase ofthe second suspension. The second suspension is then injected into ahost.

One embodiment for carrying out such a method will now be described.Vialed dry microparticles are mixed with an aqueous injection vehiclehaving a viscosity less than about 60 cp at 20° C., preferably about20-50 centipoise. The concentration of microparticles in the mixture isgreater than about 30 mg/ml, preferably about 100-400 mgmicroparticles/ml. The mixture is agitated until a homogeneoussuspension is formed. The homogeneous suspension is withdrawn into afirst hypodermic syringe. The first syringe is connected to a secondsyringe containing a viscosity enhancing agent. A viscosity enhancingagent suitable for use with the present invention is sodiumcarboxymethyl cellulose (CMC), preferably having a viscosity of fromabout 1000 to about 2000 cp at 20° C. It should be understood that thepresent invention is not limited to the use of CMC as the viscosityenhancing agent, and other suitable viscosity enhancing agents may beused. The added volume of the viscosity enhancing agent is approximately10-25% of the volume of the microparticle suspension.

The microparticle suspension and the viscosity enhancing agent are mixedto form the injectable composition by repeatedly passing themicroparticle suspension and the viscosity enhancing agent between thefirst and second syringes. Such a syringe-syringe mixing method was usedin the injectability tests described in U.S. Pat. No. 7,799,345. Aftermixing with the viscosity enhancing agent, the viscosity of the fluidphase of the microparticle suspension is from about 200 cp to about 600cp at 20° C. A hypodermic needle is attached to the syringe containingthe injectable composition, and the injectable composition is injectedinto a host in a manner well known to one of skill in the art.

An alternate embodiment for carrying out the method of the presentinvention will now be described. Dry microparticles are mixed with anaqueous injection vehicle having a viscosity of less than about 60 cp at20° C. to form a suspension. The viscosity of the fluid phase of thesuspension is changed in a manner that will be described in more detailbelow. The suspension that constitutes the injectable composition iswithdrawn into a syringe, and the injectable composition is injectedfrom the syringe into the host. Preferably, the viscosity of the fluidphase of the suspension is changed after the suspension has beenwithdrawn into the syringe.

In one aspect of this alternate embodiment, the viscosity is changed bychanging the temperature of the fluid phase of the injectablesuspension. The methods and techniques for changing the viscosity of aliquid by changing the temperature of the liquid are readily apparent toone skilled in the art. The temperature of the fluid phase of thesuspension is changed until the desired viscosity of the fluid phase hasbeen reached. The suspension now has the desired fluid phase viscosityfor injection into a host, and constitutes the injectable composition.At this point, the suspension is withdrawn into the syringe and injectedinto the host. Alternatively, the suspension can be withdrawn into thesyringe prior to changing the temperature of the fluid phase of thesuspension to achieve the desired fluid phase viscosity. For example, aninjection vehicle that comprises a polymer solution can be used as theviscosity of polymer solutions is temperature-dependent. A polymersolution can be used to suspend the microparticles under low-viscosityconditions suitable for wetting and suspension formation. Once themicroparticles are suspended, the suspension is drawn up into a syringe.The temperature is then changed to induce higher viscosity in theinjection vehicle constituting the fluid phase of the suspension, andthe suspension having increased viscosity is injected into a host.

In another aspect of this alternate embodiment, the viscosity is changedby adding a viscosity enhancing agent to the suspension. The suspensionis withdrawn into the syringe, and then the viscosity enhancing agent isadded to the suspension in the syringe, thereby increasing the viscosityof the aqueous injection vehicle constituting the fluid phase of thesuspension. The suspension now has the desired fluid phase viscosity forinjection into a host, and constitutes the injectable composition. Thesuspension is then injected into the host. Preferably, the viscosityenhancing agent is added to the suspension immediately prior toinjection into the host. Suitable viscosity enhancing agents includesodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), such asPLASDONE, available from GAF Chemicals Corp., Wayne, N.J., andhydroxypropylmethylcellulose (HPMC), such as Methocel, available fromDow Chemical Co., Midland, Mich. However, other viscosity enhancingagents may be used, as would be readily apparent to one of skill in theart.

In another embodiment of the invention, the injectable compositions ofthe present invention are prepared by providing microparticles thatcomprise a polymeric binder and that have a mass median diameter of atleast about 10 μm. The mass median diameter of the microparticles ispreferably less than about 250 μm, and more preferably, in the range offrom about 20 μm to about 150 μm. Such microparticles can be made in themanner disclosed and described herein, or in any other manner known toone skilled in the art. An aqueous injection vehicle is provided. Suchan aqueous injection vehicle can be made in the manner disclosed anddescribed herein, or in any other manner known to one skilled in theart. The microparticles are suspended in the aqueous injection vehicleat a concentration of greater than about 30 mg/ml to form a suspension,the fluid phase of the suspension having a viscosity of at least 20 cpat 20° C.

In yet a further embodiment of the present invention, dry microparticlesare mixed with an aqueous injection vehicle containing a viscosityenhancing agent to form a suspension. Suitable viscosity enhancingagents include sodium carboxymethyl cellulose, polyvinylpyrrolidone(PVP), such as PLASDONE, available from GAF Chemicals Corp., Wayne,N.J., and hydroxypropylmethylcellulose (HPMC), such as Methocel,available from Dow Chemical Co., Midland, Mich. However, other viscosityenhancing agents may be used, as would be readily apparent to one ofskill in the art. The suspension is then dispensed into vials. The vialsare lyophilized (or vacuum dried) to remove the water. Prior toinjection, the vial contents are reconstituted with sterile water forinjection in a quantity sufficient to achieve the desired viscosity forthe fluid phase of the reconstituted injectable suspension. Preferably,the vial contents are reconstituted with a quantity of sterile water forinjection sufficient to achieve a viscosity of a fluid phase of theinjectable suspension that provides injectability of the compositionthrough a needle ranging in diameter from 18-22 gauge.

Example 2 Injectable Compositions

The injectable compositions of the present invention will now bedescribed. The injectable compositions of the present invention aresuitable for injection through a needle into a host. Injectablecomposition of microparticulated naltrexone is most preferred.Naltrexone can be prepared in accordance with the teachings of U.S. Pat.No. 6,495,164, the entirety of which is incorporated herein byreference.

In one embodiment, the injectable compositions comprise microparticlesconsisting naltrexone and polymeric binder suspended in an aqueousinjection vehicle. The injectable compositions further compriseanti-inflammatory steroidal agent mixed in the aqueous injectionvehicle. In another embodiment the injectable compositions comprisemicroparticles encapsulating naltrexone, polymeric binder andanti-inflammatory steroidal agent and suspended in an aqueous injectionvehicle. The microparticles preferably have a mass median diameter of atleast about 10 μm to about 250 μm, preferably in the range of from about20 μm to about 150 μm. However, it should be understood that theinvention is not limited to microparticles in this size range, and thatsmaller or larger microparticles may also be used. The polymeric binderis selected from the group consisting of poly(glycolic acid),poly-d,l-lactic acid, poly-l-lactic acid, copolymers of the foregoing,poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone,polydioxanone, poly(ortho carbonates), poly(acetals), poly(lacticacid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone),polyanhydrides, and polyphosphazines.

The injectable compositions comprise a therapeutically acceptable amountof naltrexone and a physiologically effective amount ofanti-inflammatory steroidal agent. The amounts of the active ingredientsshall be acceptable in conventional, non-conventional or futuretherapeutic use.

In a further embodiment another opioid antagonist buprenorohine ispreferred. Similar to preparation of encapsulating naltrexone asdetailed above, microparticular form of buprenorphbine is prepared inthis embodiment. Specifically, the injectable compositions comprisemicroparticles consisting buprenorphine and polymeric binder suspendedin an aqueous injection vehicle. The injectable compositions furthercomprise anti-inflammatory steroidal agent mixed in the aqueousinjection vehicle. In another embodiment the injectable compositionscomprise microparticles consisting polymeric binder encapsulatingbuprenorphine, and anti-inflammatory steroidal agent and suspended in anaqueous injection vehicle. The microparticles preferably have a massmedian diameter of at least about 10 μm to about 250 μm, preferably inthe range of from about 20 μm to about 150 μm. However, it should beunderstood that the invention is not limited to microparticles in thissize range, and that smaller or larger microparticles may also be used.

The injectable compositions comprise a therapeutically acceptable amountof buprenorphine and a physiologically effective amount ofanti-inflammatory steroidal agent. The amounts of the active ingredientsshall be acceptable in conventional, non-conventional or futuretherapeutic use.

The microparticles preferably comprise a polymeric binder. Suitablepolymeric binder materials include poly(glycolic acid), poly-d,l-lacticacid, poly-l-lactic acid, copolymers of the foregoing, poly(aliphaticcarboxylic acids), copolyoxalates, polycaprolactone, polydioxanone,poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone),polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides,polyphosphazines, albumin, casein, and waxes. Poly(d,l-lactic-co-glycolic acid) is commercially available from Alkermes,Inc. (Blue Ash, Ohio). A suitable product commercially available fromAlkermes, Inc. is a 50:50 poly(d,l-lactic-co-glycolic acid) known asMEDISORB® 5050 DL. This product has a mole percent composition of 50%lactide and 50% glycolide. Other suitable commercially availableproducts are MEDISORB® 6535 DL, 7525 DL, 8515 DL and poly(d,l-lacticacid) (100 DL). Poly(lactide-co-glycolides) are also commerciallyavailable from Boehringer Ingelheim (Germany) under its Resomer® mark,e.g., PLGA 50:50 (Resomer® RG 502), PLGA 75:25 (Resomer® RG 752) andd,l-PLA (Resomer® RG 206), and from Birmingham Polymers (Birmingham,Ala.). These copolymers are available in a wide range of molecularweights and ratios of lactic acid to glycolic acid.

One type of microparticle suitable for use with the present invention isa sustained-release microparticle that is biodegradable. However, itshould be understood by one skilled in the art that the presentinvention is not limited to biodegradable or other types ofsustained-release microparticles. As would be apparent to one skilled inthe art, the molecular weight of the polymeric binder material forbiodegradable microparticles is of some importance. The molecular weightshould be high enough to permit the formation of satisfactory polymercoatings, i.e., the polymer should be a good film former. Usually, asatisfactory molecular weight is in the range of 5,000 to 500,000daltons, preferably about 150,000 daltons. However, since the propertiesof the film are also partially dependent on the particular polymericbinder material being used, it is very difficult to specify anappropriate molecular weight range for all polymers. The molecularweight of the polymer is also important from the point of view of itsinfluence upon the biodegradation rate of the polymer. For a diffusionalmechanism of drug release, the polymer should remain intact until all ofthe drug is released from the microparticles and then degrade. The drugcan also be released from the microparticles as the polymeric binderbioerodes. By an appropriate selection of polymeric materials amicroparticle formulation can be made in which the resultingmicroparticles exhibit both diffusional release and biodegradationrelease properties. This is useful in according multiphasic releasepatterns.

The microparticles may include an active agent or other type ofsubstance that is released from the microparticles into the host. Suchactive agents can include 1,2-benzazoles, more particularly,3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles.The most preferred active agents of this kind are3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(“risperidone”) and3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(“9-hydroxyrisperidone”) and the pharmaceutically acceptable saltsthereof. Risperidone (which term, as used herein, is intended to includeits pharmaceutically acceptable salts) is most preferred. Risperidonecan be prepared in accordance with the teachings of U.S. Pat. No.4,804,663, the entirety of which is incorporated herein by reference.9-hydroxyrisperidone can be prepared in accordance with the teachings ofU.S. Pat. No. 5,158,952, the entirety of which is incorporated herein byreference.

Other biologically active agents include non-steroidal antifertilityagents; parasympathomimetic agents; psychotherapeutic agents;tranquilizers; decongestants; sedative hypnotics; steroids;sulfonamides; sympathomimetic agents; vaccines; vitamins; antimalarials;anti-migraine agents; anti-Parkinson agents such as L-dopa;anti-spasmodics; anticholinergic agents (e.g. oxybutynin); antitussives;bronchodilators; cardiovascular agents such as coronary vasodilators andnitroglycerin; alkaloids; analgesics; narcotics such as codeine,dihydrocodienone, meperidine, morphine and the like; non-narcotics suchas salicylates, aspirin, acetaminophen, d-propoxyphene and the like;opioid receptor antagonists, such as naltrexone and naloxone;antibiotics such as gentamycin, tetracycline and penicillins;anti-cancer agents; anti-convulsants; anti-emetics; antihistamines;anti-inflammatory agents such as hormonal agents, hydrocortisone,prednisolone, prednisone, non-hormonal agents, allopurinol,indomethacin, phenylbutazone and the like; prostaglandins and cytotoxicdrugs.

Still other suitable active agents include estrogens, antibacterials;antifungals; antivirals; anticoagulants; anticonvulsants;antidepressants; antihistamines; and immunological agents.

Other examples of suitable biologically active agents include peptidesand proteins, analogs, muteins, and active fragments thereof, such asimmunoglobulins, antibodies, cytokines (e.g. lymphokines, monokines,chemokines), blood clotting factors, hemopoietic factors, interleukins(IL-2, IL-3, IL-4, IL-6), interferons (β-IFN, α-IFN and γ-IFN),erythropoietin, nucleases, tumor necrosis factor, colony stimulatingfactors (e.g., GCSF, GM-CSF, MCSF), insulin, enzymes (e.g., superoxidedismutase, tissue plasminogen activator), tumor suppressors, bloodproteins, hormones and hormone analogs (e.g., growth hormone,adrenocorticotropic hormone and luteinizing hormone releasing hormone(LHRH)), vaccines (e.g., tumoral, bacterial and viral antigens);somatostatin; antigens; blood coagulation factors; growth factors (e.g.,nerve growth factor, insulin-like growth factor); protein inhibitors,protein antagonists, and protein agonists; nucleic acids, such asantisense molecules; oligonucleotides; and ribozymes. Small molecularweight agents suitable for use in the invention include, antitumoragents such as bleomycin hydrochloride, carboplatin, methotrexate andadriamycin; antipyretic and analgesic agents; antitussives andexpectorants such as ephedrine hydrochloride, methylephedrinehydrochloride, noscapine hydrochloride and codeine phosphate; sedativessuch as chlorpromazine hydrochloride, prochlorperazine hydrochloride andatropine sulfate; muscle relaxants such as tubocurarine chloride;antiepileptics such as sodium phenyloin and ethosuximide; antiulceragents such as metoclopramide; antidepressants such as clomipramine;antiallergic agents such as diphenhydramine; cardiotonics such astheophillol; antiarrhythmic agents such as propranolol hydrochloride;vasodilators such as diltiazem hydrochloride and bamethan sulfate;hypotensive diuretics such as pentolinium and ecarazine hydrochloride;antidiuretic agents such as metformin; anticoagulants such as sodiumcitrate and heparin; hemostatic agents such as thrombin, menadionesodium bisulfite and acetomenaphthone; antituberculous agents such asisoniazide and ethanbutol; hormones such as prednisolone sodiumphosphate and methimazole.

The microparticles can be mixed by size or by type. However, it shouldbe understood that the present invention is not limited to the use ofbiodegradable or other types of microparticles that contain an activeagent. In one embodiment, the microparticles are mixed in a manner thatprovides for the delivery of active agent to the patient in amultiphasic manner and/or in a manner that provides different activeagents to the patient at different times, or a mixture of active agentsat the same time. For example, secondary antibiotics, vaccines, or anydesired active agent, either in microparticle form or in conventional,unencapsulated form can be blended with a primary active agent andprovided to the patient.

The microparticles are preferably suspended in the injection vehicle ata concentration of greater than about 30 mg/ml. In one embodiment, themicroparticles are suspended at a concentration of from about 150 mg/mlto about 300 mg/ml. In another embodiment, the microparticles aresuspended at a concentration of from about 100 mg/ml to about 400 mg/ml.However, it should be understood that the invention is not limited to aparticular concentration.

The aqueous injection vehicle preferably has a viscosity of at least 20cp at 20° C. In one embodiment, the injection vehicle has a viscositygreater than 50 cp and less than 60 cp at 20° C. The viscosity of theinjection vehicle preferably provides injectability of the compositionthrough a needle ranging in diameter from 18-22 gauge. As known to oneskilled in the art, an 18 gauge regular wall (RW) needle has a nominalinner diameter (ID) of 0.033 in., and a 22 gauge regular wall needle hasa nominal inner diameter of 0.016 in.

The injection vehicle may comprise a viscosity enhancing agent. Apreferred viscosity enhancing agent is sodium carboxymethyl cellulose,although other suitable viscosity enhancing agents may also be used. Theinjection vehicle may also comprise a density enhancing agent thatincreases the density of the injection vehicle. A preferred densityenhancing agent is sorbitol, although other suitable density enhancingagents may also be used. The injection vehicle may also comprise atonicity adjusting agent to adjust the tonicity to preclude toxicityproblems and improve biocompatibility. A preferred tonicity adjustingagent is sodium chloride, although other suitable tonicity adjustingagents may also be used.

The injection vehicle may also comprise a wetting agent to ensurecomplete wetting of the microparticles by the injection vehicle.Preferred wetting agents include polysorbate 20 (Tween 20), polysorbate40 (Tween 40), and polysorbate 80 (Tween 80).

One preferred injection vehicle is an aqueous injection vehicle thatcomprises 1.5% sodium carboxymethyl cellulose, 30% sorbitol, and 0.2%polysorbate 20. Another preferred injection vehicle is an aqueousinjection vehicle that comprises 3% sodium carboxymethyl cellulose, 0.9%saline, and 0.1% polysorbate 20.

Example 3 Injectable Compositions—Employing ATRIGEL™ Delivery System

In yet another embodiment, instead of encapsulating the pharmaceuticalsat manufacturing, ATRIGEL™ delivery system can be employed. In thisembodiment, the pharmaceuticals are blended into ATRIGEL™ solution suchthat they are entrapped by Atrigel implant solidified upon contact withaqueous body fluid (in situ sustained release delivery). In thisembodiment, unless otherwise indicated, the ATRIGEL™ product is thethermoplastic polymer poly(lactide-co-glycolide) (PLG), thethermoplastic polymer poly(lactide-co-glycolide extended with 1,6-hexanediol) (PLG), or PLGH in the organic solvent N-methyl-2-pyrrolidone.

The injectable compositions of the present invention are typicallyadministered intravenously or intramuscularly. The timing of theinjection will vary on several factors, including the overall health ofthe subject (a human or laboratory animal), the severity of theaddiction being treated, and the like. In the case of opioid addiction,administration should be given after withdrawal symptoms havesubstantially subsided (which are often ameliorated as a result of adetoxification procedure).

CONCLUSION

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofexample only, and not limitation. The present invention is not limitedto controlled release microparticle injectable suspension, nor is itlimited to a particular active agent, polymer or solvent, nor is thepresent invention limited to a particular scale or batch size. Thus, thebreadth and scope of the present invention should not be limited by anyof the above-described exemplary embodiment, but should be defined onlyin accordance with the following claims and their equivalents.

The invention claimed is:
 1. A composition for injection into a host,consisting of: microparticles comprising essentially of an opioidantagonist and a polymeric binder selected from the group consisting ofpoly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and polyphosphazines;an injection vehicle, wherein said injection vehicle consists of water,a viscosity enhancing agent, a wetting agent, and a tonicity adjustingagent; and a steroidal anti-inflammatory agent encapsulated within saidmicroparticles.
 2. A method for treating a patient having an opioiddependency comprising parenterally administering to the patient atherapeutically effective amount of the composition of claim 1 once permonth to treat the opioid dependency.
 3. The composition of claim 1,wherein the opioid antagonist is selected from the group consisting ofnaltrexone, buprenorphine and naloxone and pharmaceutically acceptablesalts thereof and/or mixtures thereof.
 4. A method for treating apatient having an opioid dependency comprising parenterallyadministering to the patient a therapeutically effective amount of thecomposition of claim 3 once per month to treat the opioid dependency. 5.The composition of claim 1, wherein said microparticles are suspended insaid injection vehicle at a concentration of about 30 mg/ml and up toabout 300 mg/ml to form a suspension, wherein a fluid phase of saidsuspension has a viscosity greater than 30 cp and less than 600 cp at20° C., wherein the viscosity of said fluid phase of said suspensionprovides injectability of the composition into the host through a needleranging in diameter from 18-22 gauge.
 6. The composition of claim 1,wherein the steroidal anti-inflammatory agent is triamcinoloneacetonide.
 7. A method for treating a patient having an opioiddependency comprising parenterally administering to the patient atherapeutically effective amount of the composition of claim 6 once permonth to treat the opioid dependency.
 8. The composition of claim 1,wherein the polymeric binder is a copolymer of poly(glycolic acid) andpoly-d,l-lactic acid.
 9. The composition of any of claim 1, wherein theviscosity enhancing agent is sodium carboxymethyl cellulose.
 10. Thecomposition of any of claim 1, wherein the wetting agent is selectedfrom the group consisting of polysorbate 20, polysorbate 40, andpolysorbate
 80. 11. The composition of any of claim 1, wherein thetonicity adjusting agent is sodium chloride.
 12. The composition of anyclaim 1, wherein the injection vehicle consists of water, sodiumcarboxymethyl cellulose, polysorbate 20, and sodium chloride.
 13. Thecomposition of claim 1, wherein a mass median diameter of themicroparticles is about 250 μm.
 14. The composition of claim 1, whereinthe mass median diameter of the microparticles is in the range of fromabout 20 μm to about 150 μm.
 15. The composition of claim 1, wherein thepolymeric binder is poly(lactide-co-glycolide), and the injectionvehicle consists of water, sodium carboxymethyl cellulose, polysorbate20, and sodium chloride.
 16. The composition of claim 15, wherein a massmedian diameter of the microparticles is about 250 μm.
 17. Thecomposition of claim 16, wherein the mass median diameter of themicroparticles is in the range of from about 20 μm to about 150 μm. 18.The composition of claim 17, wherein the polymeric binder ispoly(d,l-lactide-co-glycolide) having a molar ratio of lactide toglycolide in the range of from about 85:15 to about 50:50.